Neurology

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

A version of this article first appeared on Medscape.com.

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

A version of this article first appeared on Medscape.com.

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

A version of this article first appeared on Medscape.com.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

To improve autism screening rates, researchers in Utah tried a range of interventions.

They added automatic reminders to the electronic health record (EHR). They started using a shorter, more sensitive screening instrument. And they trained clinicians to perform autism-specific evaluations in a primary care clinic.

Three phases

They examined more than 12,000 well-child visits for children aged 16-30 months between July 2017 and June 2019.

In all, 4,155 visits occurred at the 2 intervention clinics, and 8,078 visits occurred at the 27 community clinics in the University of Utah health care system.

From baseline through the interventions, the proportion of visits with screening increased by 51% in the intervention clinics (from 58.6% to 88.8%), and by 21% in the community clinics (from 43.4% to 52.4%). The proportion of referrals increased 1.5-fold in intervention clinics, from 1.3% to 3.3%, the authors said.

The American Academy of Pediatrics (AAP) supports screening for autism in all children starting at age 18 months, but “only 44% of children with autism have had a comprehensive autism evaluation before age 36 months,” Dr. Campbell and colleagues wrote.

In their system, about half of the children were being screened for autism, and 0.5% had autism diagnosed.

In an effort to increase the proportion of visits with screening for autism and the proportion of visits with referrals for autism evaluation, Dr. Campbell and colleagues designed a quality improvement study.

Following a baseline period, they implemented interventions in three phases.

Initially, all clinics used the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) for autism screening. For the first phase starting in July 2018, the researchers changed the screening instrument at the two intervention clinics to the Parent’s Observation of Social Interaction (POSI). This instrument “is embedded in a broadband developmental screen, is shorter than the M-CHAT-R, and includes questions about the consistency of the child’s behavior,” the authors said. “The POSI has greater sensitivity than the M-CHAT-R ... and similar, although somewhat lower, specificity.”

In intervention phase 2 starting in November 2018, the researchers “added an automatic reminder for autism screening to the EHR health maintenance screen.” Both the intervention clinics and the community clinics received the automatic reminders.

In intervention phase 3 starting in February 2019, they “added a referral option that clinicians could use for rapid access to autism-specific evaluation ... for children who had a POSI result suggestive of autism and for whom the clinician had sufficient concerns about autism that would indicate the need for referral for autism evaluation,” the researchers said.

“Using an online tutorial, we trained three clinicians in the intervention clinics to administer an observational assessment known as the Screening Tool for Autism in Toddlers (STAT),” which requires a 30-minute visit, they said. “Children who had a STAT result suggestive of autism were referred for expedited autism diagnostic evaluation, which was performed by a multidisciplinary team in our university-based developmental assessment clinic. Children who had a STAT result that did not suggest autism did not receive further autism evaluations unless the clinician felt they still needed further evaluation at the developmental clinic.”

After the switch to POSI, the percentage of visits with a positive screen result increased from 4.7% to 13.5% in the intervention clinics.

Furthermore, referrals were 3.4 times more frequent for visits during phase 3 in the intervention clinics, relative to the baseline period.
 

Potential to overwhelm

“The change to a more sensitive screening instrument increased the frequency of screening results suggestive of autism and informed our improvement team of the need to implement autism evaluation in primary care to avoid overwhelming our referral system,” Dr. Campbell and coauthors reported.

Future studies may assess whether increased screening and referrals speed the time to diagnosis and treatment and improve long-term functional abilities of children with autism. Some children in the study have received an autism diagnosis, while others have not yet been evaluated.

The use of STAT in primary care may be limited by “the barriers of training providers and purchasing materials,” the authors noted. “However, the time-based billing for lengthier appointments and billing for developmental testing help to cover cost.”

The intervention clinics and community clinics were staffed by pediatric providers, including residents and attendings, said Dr. Campbell.

“The staffing is similar at the community and intervention clinics, with mostly pediatricians and some nurse practitioners,” Dr. Campbell said. “One difference is that there are a few family medicine physicians in the community clinics, but we did not study whether that made a difference in screening. At the beginning of the study the approach to screening was the same.”

From the start, the community clinics were screening for autism and referring for further autism evaluation less often than the intervention clinics. “I don’t know why they were screening less, but they did improve with the automatic reminders,” said Dr. Campbell. “We didn’t examine type of provider or type of practice in this study, but the literature suggests that family physicians do not screen for autism as often as pediatricians.”
 

Payment and referral challenges

In theory, the approach in the study is a great idea, but it may not be feasible to implement for many private practices, said Herschel Lessin, MD. Dr. Lessin is a senior partner of the Children’s Medical Group in New York.

“We desperately need autism screening in a primary care setting,” Dr. Lessin said. “These authors found that wasn’t being done as recommended by the AAP Bright Futures, which is a problem.”

However, the researchers incorporated the interventions in a health care system with “far more resources than most people in practice would ever have” and substituted a less familiar screening tool.

In addition, the ability to use confirmatory STAT for primary care evaluations may be limited. “Unless you can find pediatricians willing to commit 30 to 45 minutes on one of these evaluations ... few are going to do that,” he said.

“The whole problem is that there are no referrals available or very few referrals available, and that insurance payments so underpay for developmental screening and evaluation that it does not justify the time doing it, so a lot of doctors are unable to do it,” said Dr. Lessin. When a referral is warranted, developmental pediatricians may have 6- to 12-month waiting lists, he said.

“For people in clinical practice, this is not news,” Dr. Lessin said. “We know we should screen for autism. The problem is it’s time consuming. Nobody pays for it. We have no place to send them even when we are suspicious.”
 

From screening to diagnosis to treatment

“Autism screen approaches vary but with educational efforts on the part of the AAP, CDC, and family organizations the rates for autism screening have dramatically improved,” said Susan L. Hyman, MD, professor of pediatrics at the University of Rochester in New York. “I do not know if screening rates have been impacted by COVID.”

Dr. Hyman and coauthors wrote an AAP clinical report on the identification, evaluation, and management of children with autism spectrum disorder. The report was published in the January 2020 issue of Pediatrics.

After screening and diagnostic testing, patients most importantly need to be able to access “timely and equitable evidence-based intervention,” which should be available, said Dr. Hyman.

Although researchers have proposed training primary care providers in autism diagnostics, “older, more complex patients with co-occurring behavioral health or other developmental disorders may need more specialized diagnostic assessment than could be accomplished in a primary care setting,” Dr. Hyman added.

“However, it is very important to identify children with therapeutic needs as early as possible and move them through the continuum from screening to diagnosis to treatment in a timely fashion. It would be wonderful if symptoms could be addressed without the need for diagnosis in the very youngest children,” Dr. Hyman said. “Early symptoms, even if not autism, are likely to be appropriate for intervention – whether it is speech therapy, attention to food selectivity, sleep problems – things that impact quality of life and potential future symptoms.”

The research was supported by the Utah Stimulating Access to Research in Residency Transition Scholar award, which is funded by the National Institutes of Health.

Dr. Campbell is an inventor on a patent related to screening for autism. The study authors otherwise had no disclosures. Dr. Lessin is on the editorial advisory board for Pediatric News and is on an advisory board for Cognoa, which is developing a medical device to diagnose autism and he is also the co-editor of the AAP's current ADHD Toolkit. Dr. Hyman had no relevant financial disclosures.

jremaly@mdedge.com

*This story was updated on Feb. 11, 2021.

To improve autism screening rates, researchers in Utah tried a range of interventions.

They added automatic reminders to the electronic health record (EHR). They started using a shorter, more sensitive screening instrument. And they trained clinicians to perform autism-specific evaluations in a primary care clinic.

Three phases

They examined more than 12,000 well-child visits for children aged 16-30 months between July 2017 and June 2019.

In all, 4,155 visits occurred at the 2 intervention clinics, and 8,078 visits occurred at the 27 community clinics in the University of Utah health care system.

From baseline through the interventions, the proportion of visits with screening increased by 51% in the intervention clinics (from 58.6% to 88.8%), and by 21% in the community clinics (from 43.4% to 52.4%). The proportion of referrals increased 1.5-fold in intervention clinics, from 1.3% to 3.3%, the authors said.

The American Academy of Pediatrics (AAP) supports screening for autism in all children starting at age 18 months, but “only 44% of children with autism have had a comprehensive autism evaluation before age 36 months,” Dr. Campbell and colleagues wrote.

In their system, about half of the children were being screened for autism, and 0.5% had autism diagnosed.

In an effort to increase the proportion of visits with screening for autism and the proportion of visits with referrals for autism evaluation, Dr. Campbell and colleagues designed a quality improvement study.

Following a baseline period, they implemented interventions in three phases.

Initially, all clinics used the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) for autism screening. For the first phase starting in July 2018, the researchers changed the screening instrument at the two intervention clinics to the Parent’s Observation of Social Interaction (POSI). This instrument “is embedded in a broadband developmental screen, is shorter than the M-CHAT-R, and includes questions about the consistency of the child’s behavior,” the authors said. “The POSI has greater sensitivity than the M-CHAT-R ... and similar, although somewhat lower, specificity.”

In intervention phase 2 starting in November 2018, the researchers “added an automatic reminder for autism screening to the EHR health maintenance screen.” Both the intervention clinics and the community clinics received the automatic reminders.

In intervention phase 3 starting in February 2019, they “added a referral option that clinicians could use for rapid access to autism-specific evaluation ... for children who had a POSI result suggestive of autism and for whom the clinician had sufficient concerns about autism that would indicate the need for referral for autism evaluation,” the researchers said.

“Using an online tutorial, we trained three clinicians in the intervention clinics to administer an observational assessment known as the Screening Tool for Autism in Toddlers (STAT),” which requires a 30-minute visit, they said. “Children who had a STAT result suggestive of autism were referred for expedited autism diagnostic evaluation, which was performed by a multidisciplinary team in our university-based developmental assessment clinic. Children who had a STAT result that did not suggest autism did not receive further autism evaluations unless the clinician felt they still needed further evaluation at the developmental clinic.”

After the switch to POSI, the percentage of visits with a positive screen result increased from 4.7% to 13.5% in the intervention clinics.

Furthermore, referrals were 3.4 times more frequent for visits during phase 3 in the intervention clinics, relative to the baseline period.
 

Potential to overwhelm

“The change to a more sensitive screening instrument increased the frequency of screening results suggestive of autism and informed our improvement team of the need to implement autism evaluation in primary care to avoid overwhelming our referral system,” Dr. Campbell and coauthors reported.

Future studies may assess whether increased screening and referrals speed the time to diagnosis and treatment and improve long-term functional abilities of children with autism. Some children in the study have received an autism diagnosis, while others have not yet been evaluated.

The use of STAT in primary care may be limited by “the barriers of training providers and purchasing materials,” the authors noted. “However, the time-based billing for lengthier appointments and billing for developmental testing help to cover cost.”

The intervention clinics and community clinics were staffed by pediatric providers, including residents and attendings, said Dr. Campbell.

“The staffing is similar at the community and intervention clinics, with mostly pediatricians and some nurse practitioners,” Dr. Campbell said. “One difference is that there are a few family medicine physicians in the community clinics, but we did not study whether that made a difference in screening. At the beginning of the study the approach to screening was the same.”

From the start, the community clinics were screening for autism and referring for further autism evaluation less often than the intervention clinics. “I don’t know why they were screening less, but they did improve with the automatic reminders,” said Dr. Campbell. “We didn’t examine type of provider or type of practice in this study, but the literature suggests that family physicians do not screen for autism as often as pediatricians.”
 

Payment and referral challenges

In theory, the approach in the study is a great idea, but it may not be feasible to implement for many private practices, said Herschel Lessin, MD. Dr. Lessin is a senior partner of the Children’s Medical Group in New York.

“We desperately need autism screening in a primary care setting,” Dr. Lessin said. “These authors found that wasn’t being done as recommended by the AAP Bright Futures, which is a problem.”

However, the researchers incorporated the interventions in a health care system with “far more resources than most people in practice would ever have” and substituted a less familiar screening tool.

In addition, the ability to use confirmatory STAT for primary care evaluations may be limited. “Unless you can find pediatricians willing to commit 30 to 45 minutes on one of these evaluations ... few are going to do that,” he said.

“The whole problem is that there are no referrals available or very few referrals available, and that insurance payments so underpay for developmental screening and evaluation that it does not justify the time doing it, so a lot of doctors are unable to do it,” said Dr. Lessin. When a referral is warranted, developmental pediatricians may have 6- to 12-month waiting lists, he said.

“For people in clinical practice, this is not news,” Dr. Lessin said. “We know we should screen for autism. The problem is it’s time consuming. Nobody pays for it. We have no place to send them even when we are suspicious.”
 

From screening to diagnosis to treatment

“Autism screen approaches vary but with educational efforts on the part of the AAP, CDC, and family organizations the rates for autism screening have dramatically improved,” said Susan L. Hyman, MD, professor of pediatrics at the University of Rochester in New York. “I do not know if screening rates have been impacted by COVID.”

Dr. Hyman and coauthors wrote an AAP clinical report on the identification, evaluation, and management of children with autism spectrum disorder. The report was published in the January 2020 issue of Pediatrics.

After screening and diagnostic testing, patients most importantly need to be able to access “timely and equitable evidence-based intervention,” which should be available, said Dr. Hyman.

Although researchers have proposed training primary care providers in autism diagnostics, “older, more complex patients with co-occurring behavioral health or other developmental disorders may need more specialized diagnostic assessment than could be accomplished in a primary care setting,” Dr. Hyman added.

“However, it is very important to identify children with therapeutic needs as early as possible and move them through the continuum from screening to diagnosis to treatment in a timely fashion. It would be wonderful if symptoms could be addressed without the need for diagnosis in the very youngest children,” Dr. Hyman said. “Early symptoms, even if not autism, are likely to be appropriate for intervention – whether it is speech therapy, attention to food selectivity, sleep problems – things that impact quality of life and potential future symptoms.”

The research was supported by the Utah Stimulating Access to Research in Residency Transition Scholar award, which is funded by the National Institutes of Health.

Dr. Campbell is an inventor on a patent related to screening for autism. The study authors otherwise had no disclosures. Dr. Lessin is on the editorial advisory board for Pediatric News and is on an advisory board for Cognoa, which is developing a medical device to diagnose autism and he is also the co-editor of the AAP's current ADHD Toolkit. Dr. Hyman had no relevant financial disclosures.

jremaly@mdedge.com

*This story was updated on Feb. 11, 2021.

To improve autism screening rates, researchers in Utah tried a range of interventions.

They added automatic reminders to the electronic health record (EHR). They started using a shorter, more sensitive screening instrument. And they trained clinicians to perform autism-specific evaluations in a primary care clinic.

Three phases

They examined more than 12,000 well-child visits for children aged 16-30 months between July 2017 and June 2019.

In all, 4,155 visits occurred at the 2 intervention clinics, and 8,078 visits occurred at the 27 community clinics in the University of Utah health care system.

From baseline through the interventions, the proportion of visits with screening increased by 51% in the intervention clinics (from 58.6% to 88.8%), and by 21% in the community clinics (from 43.4% to 52.4%). The proportion of referrals increased 1.5-fold in intervention clinics, from 1.3% to 3.3%, the authors said.

The American Academy of Pediatrics (AAP) supports screening for autism in all children starting at age 18 months, but “only 44% of children with autism have had a comprehensive autism evaluation before age 36 months,” Dr. Campbell and colleagues wrote.

In their system, about half of the children were being screened for autism, and 0.5% had autism diagnosed.

In an effort to increase the proportion of visits with screening for autism and the proportion of visits with referrals for autism evaluation, Dr. Campbell and colleagues designed a quality improvement study.

Following a baseline period, they implemented interventions in three phases.

Initially, all clinics used the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) for autism screening. For the first phase starting in July 2018, the researchers changed the screening instrument at the two intervention clinics to the Parent’s Observation of Social Interaction (POSI). This instrument “is embedded in a broadband developmental screen, is shorter than the M-CHAT-R, and includes questions about the consistency of the child’s behavior,” the authors said. “The POSI has greater sensitivity than the M-CHAT-R ... and similar, although somewhat lower, specificity.”

In intervention phase 2 starting in November 2018, the researchers “added an automatic reminder for autism screening to the EHR health maintenance screen.” Both the intervention clinics and the community clinics received the automatic reminders.

In intervention phase 3 starting in February 2019, they “added a referral option that clinicians could use for rapid access to autism-specific evaluation ... for children who had a POSI result suggestive of autism and for whom the clinician had sufficient concerns about autism that would indicate the need for referral for autism evaluation,” the researchers said.

“Using an online tutorial, we trained three clinicians in the intervention clinics to administer an observational assessment known as the Screening Tool for Autism in Toddlers (STAT),” which requires a 30-minute visit, they said. “Children who had a STAT result suggestive of autism were referred for expedited autism diagnostic evaluation, which was performed by a multidisciplinary team in our university-based developmental assessment clinic. Children who had a STAT result that did not suggest autism did not receive further autism evaluations unless the clinician felt they still needed further evaluation at the developmental clinic.”

After the switch to POSI, the percentage of visits with a positive screen result increased from 4.7% to 13.5% in the intervention clinics.

Furthermore, referrals were 3.4 times more frequent for visits during phase 3 in the intervention clinics, relative to the baseline period.
 

Potential to overwhelm

“The change to a more sensitive screening instrument increased the frequency of screening results suggestive of autism and informed our improvement team of the need to implement autism evaluation in primary care to avoid overwhelming our referral system,” Dr. Campbell and coauthors reported.

Future studies may assess whether increased screening and referrals speed the time to diagnosis and treatment and improve long-term functional abilities of children with autism. Some children in the study have received an autism diagnosis, while others have not yet been evaluated.

The use of STAT in primary care may be limited by “the barriers of training providers and purchasing materials,” the authors noted. “However, the time-based billing for lengthier appointments and billing for developmental testing help to cover cost.”

The intervention clinics and community clinics were staffed by pediatric providers, including residents and attendings, said Dr. Campbell.

“The staffing is similar at the community and intervention clinics, with mostly pediatricians and some nurse practitioners,” Dr. Campbell said. “One difference is that there are a few family medicine physicians in the community clinics, but we did not study whether that made a difference in screening. At the beginning of the study the approach to screening was the same.”

From the start, the community clinics were screening for autism and referring for further autism evaluation less often than the intervention clinics. “I don’t know why they were screening less, but they did improve with the automatic reminders,” said Dr. Campbell. “We didn’t examine type of provider or type of practice in this study, but the literature suggests that family physicians do not screen for autism as often as pediatricians.”
 

Payment and referral challenges

In theory, the approach in the study is a great idea, but it may not be feasible to implement for many private practices, said Herschel Lessin, MD. Dr. Lessin is a senior partner of the Children’s Medical Group in New York.

“We desperately need autism screening in a primary care setting,” Dr. Lessin said. “These authors found that wasn’t being done as recommended by the AAP Bright Futures, which is a problem.”

However, the researchers incorporated the interventions in a health care system with “far more resources than most people in practice would ever have” and substituted a less familiar screening tool.

In addition, the ability to use confirmatory STAT for primary care evaluations may be limited. “Unless you can find pediatricians willing to commit 30 to 45 minutes on one of these evaluations ... few are going to do that,” he said.

“The whole problem is that there are no referrals available or very few referrals available, and that insurance payments so underpay for developmental screening and evaluation that it does not justify the time doing it, so a lot of doctors are unable to do it,” said Dr. Lessin. When a referral is warranted, developmental pediatricians may have 6- to 12-month waiting lists, he said.

“For people in clinical practice, this is not news,” Dr. Lessin said. “We know we should screen for autism. The problem is it’s time consuming. Nobody pays for it. We have no place to send them even when we are suspicious.”
 

From screening to diagnosis to treatment

“Autism screen approaches vary but with educational efforts on the part of the AAP, CDC, and family organizations the rates for autism screening have dramatically improved,” said Susan L. Hyman, MD, professor of pediatrics at the University of Rochester in New York. “I do not know if screening rates have been impacted by COVID.”

Dr. Hyman and coauthors wrote an AAP clinical report on the identification, evaluation, and management of children with autism spectrum disorder. The report was published in the January 2020 issue of Pediatrics.

After screening and diagnostic testing, patients most importantly need to be able to access “timely and equitable evidence-based intervention,” which should be available, said Dr. Hyman.

Although researchers have proposed training primary care providers in autism diagnostics, “older, more complex patients with co-occurring behavioral health or other developmental disorders may need more specialized diagnostic assessment than could be accomplished in a primary care setting,” Dr. Hyman added.

“However, it is very important to identify children with therapeutic needs as early as possible and move them through the continuum from screening to diagnosis to treatment in a timely fashion. It would be wonderful if symptoms could be addressed without the need for diagnosis in the very youngest children,” Dr. Hyman said. “Early symptoms, even if not autism, are likely to be appropriate for intervention – whether it is speech therapy, attention to food selectivity, sleep problems – things that impact quality of life and potential future symptoms.”

The research was supported by the Utah Stimulating Access to Research in Residency Transition Scholar award, which is funded by the National Institutes of Health.

Dr. Campbell is an inventor on a patent related to screening for autism. The study authors otherwise had no disclosures. Dr. Lessin is on the editorial advisory board for Pediatric News and is on an advisory board for Cognoa, which is developing a medical device to diagnose autism and he is also the co-editor of the AAP's current ADHD Toolkit. Dr. Hyman had no relevant financial disclosures.

jremaly@mdedge.com

*This story was updated on Feb. 11, 2021.

The Food and Drug Administration has approved intramuscular (IM) administration of peginterferon beta-1a (Plegridy, Biogen) for patients with relapsing forms of multiple sclerosis (MS).

“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.

Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.

Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.

The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.

Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.

The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.

The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved intramuscular (IM) administration of peginterferon beta-1a (Plegridy, Biogen) for patients with relapsing forms of multiple sclerosis (MS).

“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.

Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.

Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.

The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.

Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.

The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.

The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved intramuscular (IM) administration of peginterferon beta-1a (Plegridy, Biogen) for patients with relapsing forms of multiple sclerosis (MS).

“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.

Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.

Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.

The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.

Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.

The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.

The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.

A version of this article first appeared on Medscape.com.

Afternoon napping was associated with better cognition in an older Chinese population, according to a new study in General Psychiatry.

The findings add to those seen in other observational studies showing afternoon napping promotes cognitive function, said the authors of the paper, published in General Psychiatry.

“The prevalence of afternoon napping has been increasing in older adults much more than in younger individuals,” wrote Han Cai, MS, of the department of geriatrics at The Fourth People’s Hospital of Wuhu, Anhui, China, and coauthors. “The elderly individuals who took afternoon naps showed significantly higher cognitive performance compared with those who did not nap.”

The researchers enrolled 2,214 people in the study – all Han Chinese and aged 60 or older. Afternoon napping was considered any period of inactivity of at least 5 minutes but less than 2 hours after lunch and outside of the person’s main sleep schedule. Those who reported ever napping – 1,534 subjects – were included in the napping group, and the others – 680 – in the nonnapping group. Patients with major physical conditions were excluded.

The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and the Neuropsychological Test Battery (NTB) were used to measure cognitive function, and 739 patients agreed to blood tests for lipid values.

The average total MMSE score was higher for the napping group at 25.3 points out of 30, than for the nonnapping group, at 24.56 (P = .003). Those in the napping group also had significantly higher scores in the orientation portion of the MoCA test, at 5.55 out of 6 points, compared with 5.41 for the nonnapping group (P = .006).

Those in the napping group scored significantly higher on the digit span and language fluency parts of the Neuropsychological Test Battery (P = .009 and .020, respectively).

Dementia was assessed with face-to-face visits with clinicians, but diagnoses of dementia were not different between the groups.

Triglycerides were found to be higher – though still in the normal range – in the napping group compared with the nonnapping group, 1.80 mmol/L to 1.75 mmol/L, the researchers found (P = .001). No differences were seen for HDL or LDL cholesterol levels, or in hypertension or diabetes, the researchers reported.

The authors noted that inflammation is likely an important feature in the relationship between napping and cognitive function. Inflammatory cytokines have been found to play a role in sleep disorders, and strong inflammatory responses can lead to adverse events, including cognitive impairment.

“Sleep is known to be a regulator of the immune response that counters these inflammatory mediators, whereas napping, in particular, is thought to be an evolved response to inflammation,” they said.

The average age of patients in the napping group was 72.8 years, slightly older than those in the nonnapping group at 71.3 years, and this was a significant difference (P = .016).

The researchers acknowledged that the study “could not show direct causality of napping, whether beneficial or harmful,” and that “a lack of detailed information regarding napping duration ... also limited the description of napping status.”

Junxin Li, PhD, RN, assistant professor at Johns Hopkins School of Nursing, Baltimore, who has studied napping and cognition, said that previous research generally supports a U-shaped relationship between napping and mental acuity, with shorter or medium-length naps benefiting cognition and no naps or naps that are too long being detrimental.

Afternoon napping was associated with better cognition in an older Chinese population, according to a new study in General Psychiatry.

The findings add to those seen in other observational studies showing afternoon napping promotes cognitive function, said the authors of the paper, published in General Psychiatry.

“The prevalence of afternoon napping has been increasing in older adults much more than in younger individuals,” wrote Han Cai, MS, of the department of geriatrics at The Fourth People’s Hospital of Wuhu, Anhui, China, and coauthors. “The elderly individuals who took afternoon naps showed significantly higher cognitive performance compared with those who did not nap.”

The researchers enrolled 2,214 people in the study – all Han Chinese and aged 60 or older. Afternoon napping was considered any period of inactivity of at least 5 minutes but less than 2 hours after lunch and outside of the person’s main sleep schedule. Those who reported ever napping – 1,534 subjects – were included in the napping group, and the others – 680 – in the nonnapping group. Patients with major physical conditions were excluded.

The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and the Neuropsychological Test Battery (NTB) were used to measure cognitive function, and 739 patients agreed to blood tests for lipid values.

The average total MMSE score was higher for the napping group at 25.3 points out of 30, than for the nonnapping group, at 24.56 (P = .003). Those in the napping group also had significantly higher scores in the orientation portion of the MoCA test, at 5.55 out of 6 points, compared with 5.41 for the nonnapping group (P = .006).

Those in the napping group scored significantly higher on the digit span and language fluency parts of the Neuropsychological Test Battery (P = .009 and .020, respectively).

Dementia was assessed with face-to-face visits with clinicians, but diagnoses of dementia were not different between the groups.

Triglycerides were found to be higher – though still in the normal range – in the napping group compared with the nonnapping group, 1.80 mmol/L to 1.75 mmol/L, the researchers found (P = .001). No differences were seen for HDL or LDL cholesterol levels, or in hypertension or diabetes, the researchers reported.

The authors noted that inflammation is likely an important feature in the relationship between napping and cognitive function. Inflammatory cytokines have been found to play a role in sleep disorders, and strong inflammatory responses can lead to adverse events, including cognitive impairment.

“Sleep is known to be a regulator of the immune response that counters these inflammatory mediators, whereas napping, in particular, is thought to be an evolved response to inflammation,” they said.

The average age of patients in the napping group was 72.8 years, slightly older than those in the nonnapping group at 71.3 years, and this was a significant difference (P = .016).

The researchers acknowledged that the study “could not show direct causality of napping, whether beneficial or harmful,” and that “a lack of detailed information regarding napping duration ... also limited the description of napping status.”

Junxin Li, PhD, RN, assistant professor at Johns Hopkins School of Nursing, Baltimore, who has studied napping and cognition, said that previous research generally supports a U-shaped relationship between napping and mental acuity, with shorter or medium-length naps benefiting cognition and no naps or naps that are too long being detrimental.

Afternoon napping was associated with better cognition in an older Chinese population, according to a new study in General Psychiatry.

The findings add to those seen in other observational studies showing afternoon napping promotes cognitive function, said the authors of the paper, published in General Psychiatry.

“The prevalence of afternoon napping has been increasing in older adults much more than in younger individuals,” wrote Han Cai, MS, of the department of geriatrics at The Fourth People’s Hospital of Wuhu, Anhui, China, and coauthors. “The elderly individuals who took afternoon naps showed significantly higher cognitive performance compared with those who did not nap.”

The researchers enrolled 2,214 people in the study – all Han Chinese and aged 60 or older. Afternoon napping was considered any period of inactivity of at least 5 minutes but less than 2 hours after lunch and outside of the person’s main sleep schedule. Those who reported ever napping – 1,534 subjects – were included in the napping group, and the others – 680 – in the nonnapping group. Patients with major physical conditions were excluded.

The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and the Neuropsychological Test Battery (NTB) were used to measure cognitive function, and 739 patients agreed to blood tests for lipid values.

The average total MMSE score was higher for the napping group at 25.3 points out of 30, than for the nonnapping group, at 24.56 (P = .003). Those in the napping group also had significantly higher scores in the orientation portion of the MoCA test, at 5.55 out of 6 points, compared with 5.41 for the nonnapping group (P = .006).

Those in the napping group scored significantly higher on the digit span and language fluency parts of the Neuropsychological Test Battery (P = .009 and .020, respectively).

Dementia was assessed with face-to-face visits with clinicians, but diagnoses of dementia were not different between the groups.

Triglycerides were found to be higher – though still in the normal range – in the napping group compared with the nonnapping group, 1.80 mmol/L to 1.75 mmol/L, the researchers found (P = .001). No differences were seen for HDL or LDL cholesterol levels, or in hypertension or diabetes, the researchers reported.

The authors noted that inflammation is likely an important feature in the relationship between napping and cognitive function. Inflammatory cytokines have been found to play a role in sleep disorders, and strong inflammatory responses can lead to adverse events, including cognitive impairment.

“Sleep is known to be a regulator of the immune response that counters these inflammatory mediators, whereas napping, in particular, is thought to be an evolved response to inflammation,” they said.

The average age of patients in the napping group was 72.8 years, slightly older than those in the nonnapping group at 71.3 years, and this was a significant difference (P = .016).

The researchers acknowledged that the study “could not show direct causality of napping, whether beneficial or harmful,” and that “a lack of detailed information regarding napping duration ... also limited the description of napping status.”

Junxin Li, PhD, RN, assistant professor at Johns Hopkins School of Nursing, Baltimore, who has studied napping and cognition, said that previous research generally supports a U-shaped relationship between napping and mental acuity, with shorter or medium-length naps benefiting cognition and no naps or naps that are too long being detrimental.

Researchers from the National Institute of Neurological Disorders and Stroke studying the brains of patients who died from COVID-19, “consistently” found microvascular damage—but no signs of COVID-19 infection. Of the 19 patients in the study, 14 had chronic illnesses, including diabetes mellitus and hypertension, and 11 had ben found dead or had died unexpectedly. Of the 16 with available medical histories, one had delirium and the others had respiratory or unknown symptoms. Two had pulmonary embolism.

                Patients with COVID-19 often have neurological problems, such as headaches, delirium, and dizziness. Some have strokes. Several studies have shown that COVID-19 can cause inflammation and blood vessel damage, but the precise mode of action is still unclear. In this study, the researchers used a magnetic resonance imaging (MRI) scanner 4 to 10 times more sensitive than most MRI scanners to examine samples of the olfactory bulbs and brainstems from the samples.

                In 9 patients, the MRI scan showed punctate hyperintensities (bright spots representing areas of microvascular injury and fibrinogen leakage) that often indicate inflammation. In 10 brains, they found punctate hypointensities (dark spots) that corresponded to congested blood vessels, with surrounding areas of fibrinogen leakage and relatively intact vasculature. Areas of linear hypointensities (dark spots) were interpreted as microhemorrhages.

                Using the scans as a guide, the researchers examined the spots more closely under a microscope. They found that the bright spots contained blood vessels that were thinner than normal and sometimes leaked blood proteins into the brain. This, the researchers say, seemed to trigger an immune reaction. The spots were surrounded by T cells from the blood and the brain’s own immune cells. In contrast, the dark spots contained clotted and leaky blood vessels but no immune response.

                Moreover, although they used several methods for detecting genetic material or proteins from SAS-CoV-2, they found none. It’s possible, the researchers say, that the virus was cleared by the time of death or that viral copy numbers were undetectable by their assays.

                We were completely surprised,” said Avindra Nath, MD, NINDS clinical director. “Originally, we expected to see damage that is caused by a lack of oxygen. Instead, we saw multifocal areas of damage that is usually associated with strokes and neuroinflammatory diseases.”

                In future, Nath says, they plan to study how COVID-19 harms the blood vessels and whether that produces some of the short- and long-term symptoms seen. “We hope these results will help doctors understand the full spectrum of problems patients may suffer so that we can come up with better treatments.”

Researchers from the National Institute of Neurological Disorders and Stroke studying the brains of patients who died from COVID-19, “consistently” found microvascular damage—but no signs of COVID-19 infection. Of the 19 patients in the study, 14 had chronic illnesses, including diabetes mellitus and hypertension, and 11 had ben found dead or had died unexpectedly. Of the 16 with available medical histories, one had delirium and the others had respiratory or unknown symptoms. Two had pulmonary embolism.

                Patients with COVID-19 often have neurological problems, such as headaches, delirium, and dizziness. Some have strokes. Several studies have shown that COVID-19 can cause inflammation and blood vessel damage, but the precise mode of action is still unclear. In this study, the researchers used a magnetic resonance imaging (MRI) scanner 4 to 10 times more sensitive than most MRI scanners to examine samples of the olfactory bulbs and brainstems from the samples.

                In 9 patients, the MRI scan showed punctate hyperintensities (bright spots representing areas of microvascular injury and fibrinogen leakage) that often indicate inflammation. In 10 brains, they found punctate hypointensities (dark spots) that corresponded to congested blood vessels, with surrounding areas of fibrinogen leakage and relatively intact vasculature. Areas of linear hypointensities (dark spots) were interpreted as microhemorrhages.

                Using the scans as a guide, the researchers examined the spots more closely under a microscope. They found that the bright spots contained blood vessels that were thinner than normal and sometimes leaked blood proteins into the brain. This, the researchers say, seemed to trigger an immune reaction. The spots were surrounded by T cells from the blood and the brain’s own immune cells. In contrast, the dark spots contained clotted and leaky blood vessels but no immune response.

                Moreover, although they used several methods for detecting genetic material or proteins from SAS-CoV-2, they found none. It’s possible, the researchers say, that the virus was cleared by the time of death or that viral copy numbers were undetectable by their assays.

                We were completely surprised,” said Avindra Nath, MD, NINDS clinical director. “Originally, we expected to see damage that is caused by a lack of oxygen. Instead, we saw multifocal areas of damage that is usually associated with strokes and neuroinflammatory diseases.”

                In future, Nath says, they plan to study how COVID-19 harms the blood vessels and whether that produces some of the short- and long-term symptoms seen. “We hope these results will help doctors understand the full spectrum of problems patients may suffer so that we can come up with better treatments.”

Researchers from the National Institute of Neurological Disorders and Stroke studying the brains of patients who died from COVID-19, “consistently” found microvascular damage—but no signs of COVID-19 infection. Of the 19 patients in the study, 14 had chronic illnesses, including diabetes mellitus and hypertension, and 11 had ben found dead or had died unexpectedly. Of the 16 with available medical histories, one had delirium and the others had respiratory or unknown symptoms. Two had pulmonary embolism.

                Patients with COVID-19 often have neurological problems, such as headaches, delirium, and dizziness. Some have strokes. Several studies have shown that COVID-19 can cause inflammation and blood vessel damage, but the precise mode of action is still unclear. In this study, the researchers used a magnetic resonance imaging (MRI) scanner 4 to 10 times more sensitive than most MRI scanners to examine samples of the olfactory bulbs and brainstems from the samples.

                In 9 patients, the MRI scan showed punctate hyperintensities (bright spots representing areas of microvascular injury and fibrinogen leakage) that often indicate inflammation. In 10 brains, they found punctate hypointensities (dark spots) that corresponded to congested blood vessels, with surrounding areas of fibrinogen leakage and relatively intact vasculature. Areas of linear hypointensities (dark spots) were interpreted as microhemorrhages.

                Using the scans as a guide, the researchers examined the spots more closely under a microscope. They found that the bright spots contained blood vessels that were thinner than normal and sometimes leaked blood proteins into the brain. This, the researchers say, seemed to trigger an immune reaction. The spots were surrounded by T cells from the blood and the brain’s own immune cells. In contrast, the dark spots contained clotted and leaky blood vessels but no immune response.

                Moreover, although they used several methods for detecting genetic material or proteins from SAS-CoV-2, they found none. It’s possible, the researchers say, that the virus was cleared by the time of death or that viral copy numbers were undetectable by their assays.

                We were completely surprised,” said Avindra Nath, MD, NINDS clinical director. “Originally, we expected to see damage that is caused by a lack of oxygen. Instead, we saw multifocal areas of damage that is usually associated with strokes and neuroinflammatory diseases.”

                In future, Nath says, they plan to study how COVID-19 harms the blood vessels and whether that produces some of the short- and long-term symptoms seen. “We hope these results will help doctors understand the full spectrum of problems patients may suffer so that we can come up with better treatments.”

EVIDENCE SUMMARY

Higher odds of depression in youth and adolescents with concussion

A 2019 prospective cohort study used data from the 2017 Nevada Youth Risk Behavior Surveillance Survey (YRBSS) to evaluate the relationship between concussion and depression in high school students.¹ Included students were physically active for at least 60 minutes on 5 or more days per week or played on at least 1 sports team (N = 3427; 9th-12th grade students from 98 schools). When compared to the total population of included students and controlled for covariates, those who self-reported a concussion within the past 12 months (N = 664) had a higher adjusted odds ratio (aOR) of depressive symptoms (aOR = 1.5; 95% confidence interval [CI], 1.1-1.9). Depressive symptoms were reported in 38.1% of patients with a history of concussion, compared to 29.2% of patients who did not report a concussion in the past 12 months.

A 2014 retrospective cohort study examined data from the 2007-2008 National Survey of Children’s Health and evaluated the association between previous concussion and current depression diagnosis in youth ages 12 to 17 years without a current concussion (N = 36,060).² Parents were contacted by random-digit dialing, prompted with a description of depression, and asked if their child currently had a clinical diagnosis of depression and whether a concussion had ever been diagnosed. A prior diagnosis of concussion was associated with greater risk for current depression compared to youth with no concussion history (aOR = 3.3; 95% CI, 2-5.5). Current depression was reported in 10.1% of patients with a history of concussion compared to 3.4% of patients with no history of concussion.

Findings vary among college athletes

A 2015 case-control study examined the prevalence of depressive symptoms in college athletes diagnosed with concussion compared to an athletic control group.³ The intervention group (N = 84; 77% male; average age, 18.4 years) received a concussion diagnosis from the team physician or certified athletic trainer. The athletic control group (N = 42; 55% male; average age, 18.9 years) reported no concussions in the past year.

The Beck Depression Inventory–Fast Screen (BDI-FS) was administered to the concussion group at baseline and postconcussion, and to the control group at 2 time points, with an average interval of 6.8 weeks. A score of ≥ 4 on the BDI-FS (scoring range, 0-21; higher score suggestive of more severe depression) indicated athletes at risk for depression. Concussed athletes exhibited a statistically significant increase in depression symptoms compared to control participants (20% vs 5%; x²₁ = 5.2; P = .02).

A 2018 cross-sectional study examined the association between concussion and adverse health outcomes in former college football players who played at least 1 year in college (1999-2001) but had no professional football experience.⁴ The cohort (N = 204; average age, 35) self-reported (15 years after their college career ended) the number of concussions sustained during high school and college sports performance. Reports were then stratified into 3 categories: no concussions, 1 or 2 concussions, and ≥ 3 concussions. The Patient Health Questionnaire (PHQ-9) was used to screen for depression, with scores categorized to no or mild depression (< 10) and moderate-to-­severe depression (≥ 10).

Controlling for body mass index, athletes reporting ≥ 3 concussions had a higher prevalence of depression compared to those reporting no concussions (prevalence ratio [PR] = 4.2; 95% CI, 1.0-16.3) or 1 to 2 concussions (PR = 2.8; 95% CI, 1.3-6.0). No statistically significant association between concussion and depression was observed with athletes reporting 1 to 2 concussions compared to 0 concussions.

The exact relationship— degree and context— between concussion and depression remains vague.

A 2015 prospective longitudinal cohort study examined postinjury depressive symptoms in 3 groups of Division 1 male and female college student athletes (N = 21; ages 18-22).⁵ Physician-diagnosed ­concussed (N = 7) and injured but nonconcussed (N = 7) athletes completed the Center for Epidemiological Studies Depression Scale (CES-D) at baseline and at 1 week, 1 month, and 3 months postinjury. Sport-matched healthy athletes (N = 7) completed it only at baseline. A CES-D score of ≥ 16 (range, 0-60) indicated a risk for clinical depression. Participants with a history of depression or other injury resulting in ≥ 1 day of time lost within the past 3 months were excluded.

Continue to: While both groups...

While both groups showed a significant increase from baseline CES-D scores, there were no significant differences in depressive symptoms between concussed (mean CES-D score ± standard deviation [SD]: baseline, 6.7 ± 3.9; 1 week, 11 ± 5.3; 1 month, 8.3 ± 5; 3 months, 6.4 ± 5.4) and injured but nonconcussed participants (mean CES-D score ± SD: baseline, 5.7 ± 2.8; 1 week, 9.1 ± 4; 1 month, 8.9 ± 4.6; 3 months, 6.9 ± 2.8) at any of the postinjury time points.

Findings among semipro and pro athletes appear to vary by sport

A 2016 prospective cohort study assessed the impact of concussive events on incidence of depression in active semiprofessional and professional football players who had previously sustained ≥ 1 concussions.⁶ Participants (N = 27) answered an anonymous online survey that included the revised version of the CES-D (CESD-R) to determine level of depression (a score of ≥ 16 defined clinical depression). Players with a CESD-R score ≥ 16 (N = 16) sustained a significantly greater average number of concussions compared to those who scored < 16 (N = 11; 3.8 vs. 1.6, P = .0004). Players who sustained ≥ 3 concussions scored significantly higher on the CESD-R than players with ≤ 2 concussions (average score, 24 vs 15.6; P = .03).

A 2017 case-control study examined the long-term health outcomes of retired Scottish male rugby players (N = 52; mean age, 54 years) with a history of mild concussion compared to males of similar age with no previous history of concussion (N = 29; mean age, 55).⁷ The Hospital Anxiety and Depression Scale (HADS) was used to assess depression on a 21-point scale (normal = 0-7; borderline, 8-10; abnormal, 11-21). There was no significant difference observed in mean HADS scores between the rugby players and controls, respectively (2.8 ± 2.1 vs 2.6 ± 2 .8; P = .941).

A 2013 case-control study of 30 retired NFL players with 29 controls matched for age, estimated IQ, and education examined the relationship between a remote history of concussion and current symptoms of depression.⁸ Concussion history was self-reported by the retired players. Controls with a history of concussion were excluded from the study. The Beck Depression Inventory-II (BDI-II) was used to measure depression symptoms, with a score of 1 to 9 designating minimal depression and ≥ 10 mild-to-moderate depression. Retired players scored significantly higher on the BDI-II compared to the controls (8.8 vs 2.8; P = .001).

Editor’s takeaway

Concussions include cognitive compromise. An astute clinician’s concern for depression as a sequela makes sense. This evidence contributes to that conjecture. However, the authors of this Clinical Inquiry correctly outline the limitations, inconsistencies, and biases of the evidence. The exact relationship—degree and context—between concussion and depression remains vague.

EVIDENCE SUMMARY

Higher odds of depression in youth and adolescents with concussion

A 2019 prospective cohort study used data from the 2017 Nevada Youth Risk Behavior Surveillance Survey (YRBSS) to evaluate the relationship between concussion and depression in high school students.¹ Included students were physically active for at least 60 minutes on 5 or more days per week or played on at least 1 sports team (N = 3427; 9th-12th grade students from 98 schools). When compared to the total population of included students and controlled for covariates, those who self-reported a concussion within the past 12 months (N = 664) had a higher adjusted odds ratio (aOR) of depressive symptoms (aOR = 1.5; 95% confidence interval [CI], 1.1-1.9). Depressive symptoms were reported in 38.1% of patients with a history of concussion, compared to 29.2% of patients who did not report a concussion in the past 12 months.

A 2014 retrospective cohort study examined data from the 2007-2008 National Survey of Children’s Health and evaluated the association between previous concussion and current depression diagnosis in youth ages 12 to 17 years without a current concussion (N = 36,060).² Parents were contacted by random-digit dialing, prompted with a description of depression, and asked if their child currently had a clinical diagnosis of depression and whether a concussion had ever been diagnosed. A prior diagnosis of concussion was associated with greater risk for current depression compared to youth with no concussion history (aOR = 3.3; 95% CI, 2-5.5). Current depression was reported in 10.1% of patients with a history of concussion compared to 3.4% of patients with no history of concussion.

Findings vary among college athletes

A 2015 case-control study examined the prevalence of depressive symptoms in college athletes diagnosed with concussion compared to an athletic control group.³ The intervention group (N = 84; 77% male; average age, 18.4 years) received a concussion diagnosis from the team physician or certified athletic trainer. The athletic control group (N = 42; 55% male; average age, 18.9 years) reported no concussions in the past year.

The Beck Depression Inventory–Fast Screen (BDI-FS) was administered to the concussion group at baseline and postconcussion, and to the control group at 2 time points, with an average interval of 6.8 weeks. A score of ≥ 4 on the BDI-FS (scoring range, 0-21; higher score suggestive of more severe depression) indicated athletes at risk for depression. Concussed athletes exhibited a statistically significant increase in depression symptoms compared to control participants (20% vs 5%; x²₁ = 5.2; P = .02).

A 2018 cross-sectional study examined the association between concussion and adverse health outcomes in former college football players who played at least 1 year in college (1999-2001) but had no professional football experience.⁴ The cohort (N = 204; average age, 35) self-reported (15 years after their college career ended) the number of concussions sustained during high school and college sports performance. Reports were then stratified into 3 categories: no concussions, 1 or 2 concussions, and ≥ 3 concussions. The Patient Health Questionnaire (PHQ-9) was used to screen for depression, with scores categorized to no or mild depression (< 10) and moderate-to-­severe depression (≥ 10).

Controlling for body mass index, athletes reporting ≥ 3 concussions had a higher prevalence of depression compared to those reporting no concussions (prevalence ratio [PR] = 4.2; 95% CI, 1.0-16.3) or 1 to 2 concussions (PR = 2.8; 95% CI, 1.3-6.0). No statistically significant association between concussion and depression was observed with athletes reporting 1 to 2 concussions compared to 0 concussions.

The exact relationship— degree and context— between concussion and depression remains vague.

A 2015 prospective longitudinal cohort study examined postinjury depressive symptoms in 3 groups of Division 1 male and female college student athletes (N = 21; ages 18-22).⁵ Physician-diagnosed ­concussed (N = 7) and injured but nonconcussed (N = 7) athletes completed the Center for Epidemiological Studies Depression Scale (CES-D) at baseline and at 1 week, 1 month, and 3 months postinjury. Sport-matched healthy athletes (N = 7) completed it only at baseline. A CES-D score of ≥ 16 (range, 0-60) indicated a risk for clinical depression. Participants with a history of depression or other injury resulting in ≥ 1 day of time lost within the past 3 months were excluded.

Continue to: While both groups...

While both groups showed a significant increase from baseline CES-D scores, there were no significant differences in depressive symptoms between concussed (mean CES-D score ± standard deviation [SD]: baseline, 6.7 ± 3.9; 1 week, 11 ± 5.3; 1 month, 8.3 ± 5; 3 months, 6.4 ± 5.4) and injured but nonconcussed participants (mean CES-D score ± SD: baseline, 5.7 ± 2.8; 1 week, 9.1 ± 4; 1 month, 8.9 ± 4.6; 3 months, 6.9 ± 2.8) at any of the postinjury time points.

Findings among semipro and pro athletes appear to vary by sport

A 2016 prospective cohort study assessed the impact of concussive events on incidence of depression in active semiprofessional and professional football players who had previously sustained ≥ 1 concussions.⁶ Participants (N = 27) answered an anonymous online survey that included the revised version of the CES-D (CESD-R) to determine level of depression (a score of ≥ 16 defined clinical depression). Players with a CESD-R score ≥ 16 (N = 16) sustained a significantly greater average number of concussions compared to those who scored < 16 (N = 11; 3.8 vs. 1.6, P = .0004). Players who sustained ≥ 3 concussions scored significantly higher on the CESD-R than players with ≤ 2 concussions (average score, 24 vs 15.6; P = .03).

A 2017 case-control study examined the long-term health outcomes of retired Scottish male rugby players (N = 52; mean age, 54 years) with a history of mild concussion compared to males of similar age with no previous history of concussion (N = 29; mean age, 55).⁷ The Hospital Anxiety and Depression Scale (HADS) was used to assess depression on a 21-point scale (normal = 0-7; borderline, 8-10; abnormal, 11-21). There was no significant difference observed in mean HADS scores between the rugby players and controls, respectively (2.8 ± 2.1 vs 2.6 ± 2 .8; P = .941).

A 2013 case-control study of 30 retired NFL players with 29 controls matched for age, estimated IQ, and education examined the relationship between a remote history of concussion and current symptoms of depression.⁸ Concussion history was self-reported by the retired players. Controls with a history of concussion were excluded from the study. The Beck Depression Inventory-II (BDI-II) was used to measure depression symptoms, with a score of 1 to 9 designating minimal depression and ≥ 10 mild-to-moderate depression. Retired players scored significantly higher on the BDI-II compared to the controls (8.8 vs 2.8; P = .001).

Editor’s takeaway

Concussions include cognitive compromise. An astute clinician’s concern for depression as a sequela makes sense. This evidence contributes to that conjecture. However, the authors of this Clinical Inquiry correctly outline the limitations, inconsistencies, and biases of the evidence. The exact relationship—degree and context—between concussion and depression remains vague.

EVIDENCE SUMMARY

Higher odds of depression in youth and adolescents with concussion

A 2019 prospective cohort study used data from the 2017 Nevada Youth Risk Behavior Surveillance Survey (YRBSS) to evaluate the relationship between concussion and depression in high school students.¹ Included students were physically active for at least 60 minutes on 5 or more days per week or played on at least 1 sports team (N = 3427; 9th-12th grade students from 98 schools). When compared to the total population of included students and controlled for covariates, those who self-reported a concussion within the past 12 months (N = 664) had a higher adjusted odds ratio (aOR) of depressive symptoms (aOR = 1.5; 95% confidence interval [CI], 1.1-1.9). Depressive symptoms were reported in 38.1% of patients with a history of concussion, compared to 29.2% of patients who did not report a concussion in the past 12 months.

A 2014 retrospective cohort study examined data from the 2007-2008 National Survey of Children’s Health and evaluated the association between previous concussion and current depression diagnosis in youth ages 12 to 17 years without a current concussion (N = 36,060).² Parents were contacted by random-digit dialing, prompted with a description of depression, and asked if their child currently had a clinical diagnosis of depression and whether a concussion had ever been diagnosed. A prior diagnosis of concussion was associated with greater risk for current depression compared to youth with no concussion history (aOR = 3.3; 95% CI, 2-5.5). Current depression was reported in 10.1% of patients with a history of concussion compared to 3.4% of patients with no history of concussion.

Findings vary among college athletes

A 2015 case-control study examined the prevalence of depressive symptoms in college athletes diagnosed with concussion compared to an athletic control group.³ The intervention group (N = 84; 77% male; average age, 18.4 years) received a concussion diagnosis from the team physician or certified athletic trainer. The athletic control group (N = 42; 55% male; average age, 18.9 years) reported no concussions in the past year.

The Beck Depression Inventory–Fast Screen (BDI-FS) was administered to the concussion group at baseline and postconcussion, and to the control group at 2 time points, with an average interval of 6.8 weeks. A score of ≥ 4 on the BDI-FS (scoring range, 0-21; higher score suggestive of more severe depression) indicated athletes at risk for depression. Concussed athletes exhibited a statistically significant increase in depression symptoms compared to control participants (20% vs 5%; x²₁ = 5.2; P = .02).

A 2018 cross-sectional study examined the association between concussion and adverse health outcomes in former college football players who played at least 1 year in college (1999-2001) but had no professional football experience.⁴ The cohort (N = 204; average age, 35) self-reported (15 years after their college career ended) the number of concussions sustained during high school and college sports performance. Reports were then stratified into 3 categories: no concussions, 1 or 2 concussions, and ≥ 3 concussions. The Patient Health Questionnaire (PHQ-9) was used to screen for depression, with scores categorized to no or mild depression (< 10) and moderate-to-­severe depression (≥ 10).

Controlling for body mass index, athletes reporting ≥ 3 concussions had a higher prevalence of depression compared to those reporting no concussions (prevalence ratio [PR] = 4.2; 95% CI, 1.0-16.3) or 1 to 2 concussions (PR = 2.8; 95% CI, 1.3-6.0). No statistically significant association between concussion and depression was observed with athletes reporting 1 to 2 concussions compared to 0 concussions.

The exact relationship— degree and context— between concussion and depression remains vague.

A 2015 prospective longitudinal cohort study examined postinjury depressive symptoms in 3 groups of Division 1 male and female college student athletes (N = 21; ages 18-22).⁵ Physician-diagnosed ­concussed (N = 7) and injured but nonconcussed (N = 7) athletes completed the Center for Epidemiological Studies Depression Scale (CES-D) at baseline and at 1 week, 1 month, and 3 months postinjury. Sport-matched healthy athletes (N = 7) completed it only at baseline. A CES-D score of ≥ 16 (range, 0-60) indicated a risk for clinical depression. Participants with a history of depression or other injury resulting in ≥ 1 day of time lost within the past 3 months were excluded.

Continue to: While both groups...

While both groups showed a significant increase from baseline CES-D scores, there were no significant differences in depressive symptoms between concussed (mean CES-D score ± standard deviation [SD]: baseline, 6.7 ± 3.9; 1 week, 11 ± 5.3; 1 month, 8.3 ± 5; 3 months, 6.4 ± 5.4) and injured but nonconcussed participants (mean CES-D score ± SD: baseline, 5.7 ± 2.8; 1 week, 9.1 ± 4; 1 month, 8.9 ± 4.6; 3 months, 6.9 ± 2.8) at any of the postinjury time points.

Findings among semipro and pro athletes appear to vary by sport

A 2016 prospective cohort study assessed the impact of concussive events on incidence of depression in active semiprofessional and professional football players who had previously sustained ≥ 1 concussions.⁶ Participants (N = 27) answered an anonymous online survey that included the revised version of the CES-D (CESD-R) to determine level of depression (a score of ≥ 16 defined clinical depression). Players with a CESD-R score ≥ 16 (N = 16) sustained a significantly greater average number of concussions compared to those who scored < 16 (N = 11; 3.8 vs. 1.6, P = .0004). Players who sustained ≥ 3 concussions scored significantly higher on the CESD-R than players with ≤ 2 concussions (average score, 24 vs 15.6; P = .03).

A 2017 case-control study examined the long-term health outcomes of retired Scottish male rugby players (N = 52; mean age, 54 years) with a history of mild concussion compared to males of similar age with no previous history of concussion (N = 29; mean age, 55).⁷ The Hospital Anxiety and Depression Scale (HADS) was used to assess depression on a 21-point scale (normal = 0-7; borderline, 8-10; abnormal, 11-21). There was no significant difference observed in mean HADS scores between the rugby players and controls, respectively (2.8 ± 2.1 vs 2.6 ± 2 .8; P = .941).

A 2013 case-control study of 30 retired NFL players with 29 controls matched for age, estimated IQ, and education examined the relationship between a remote history of concussion and current symptoms of depression.⁸ Concussion history was self-reported by the retired players. Controls with a history of concussion were excluded from the study. The Beck Depression Inventory-II (BDI-II) was used to measure depression symptoms, with a score of 1 to 9 designating minimal depression and ≥ 10 mild-to-moderate depression. Retired players scored significantly higher on the BDI-II compared to the controls (8.8 vs 2.8; P = .001).

Editor’s takeaway

Concussions include cognitive compromise. An astute clinician’s concern for depression as a sequela makes sense. This evidence contributes to that conjecture. However, the authors of this Clinical Inquiry correctly outline the limitations, inconsistencies, and biases of the evidence. The exact relationship—degree and context—between concussion and depression remains vague.

More people with fever and body aches are turning to NSAIDs to ease symptoms, but the drugs have come under new scrutiny as investigators work to determine whether they are a safe way to relieve the pain of COVID-19 vaccination or symptoms of the disease.

Early on in the pandemic, French health officials warned that NSAIDs, such as ibuprofen, could worsen coronavirus disease, and they recommended switching to acetaminophen instead.

The National Health Service in the United Kingdom followed with a similar recommendation for acetaminophen.

But the European Medicines Agency took a different approach, reporting “no scientific evidence” that NSAIDs could worsen COVID-19. The U.S. Food and Drug Administration also opted not to take a stance.

The debate prompted discussion on social media, with various reactions from around the world. It also inspired Craig Wilen, MD, PhD, from Yale University, New Haven, Conn., and associates to examine the effect of NSAIDs on COVID-19 infection and immune response. Their findings were published online Jan.20 in the Journal of Virology.

“It really bothered me that non–evidence-based decisions were driving the conversation,” Dr. Wilen said. “Millions of people are taking NSAIDs every day and clinical decisions about their care shouldn’t be made on a hypothesis.”

One theory is that NSAIDs alter susceptibility to infection by modifying ACE2. The drugs might also change the cell entry receptor for SARS-CoV-2, alter virus replication, or even modify the immune response.

British researchers, also questioning the safety of NSAIDs in patients with COVID-19, delved into National Health Service records to study two large groups of patients, some of whom were taking the pain relievers.

“We were watching the controversy and the lack of evidence and wanted to contribute,” lead investigator Angel Wong, PhD, from the London School of Hygiene and Tropical Medicine, said in an interview.

And with nearly 11 million NSAID prescriptions dispensed in primary care in England alone in the past 12 months, the inconsistency was concerning.

The team compared COVID-19–related deaths in two groups: one group of more than 700,000 people taking NSAIDs, including patients with rheumatoid arthritis and osteoarthritis; and another of almost 3.5 million people not on the medication.

NSAIDs work by inhibiting cyclooxygenase-1 and COX-2 enzymes in the body, which are crucial for the generation of prostaglandins. These lipid molecules play a role in inflammation and are blocked by NSAIDs.

The investigators found no evidence of a harmful effect of NSAIDs on COVID-19-related deaths; their results were published online Jan. 21 in the Annals of the Rheumatic Diseases.

The results, they pointed out, are in line with a Danish study that also showed no evidence of a higher risk for severe COVID-19 outcomes with NSAID use.

“It’s reassuring,” Dr. Wong said, “that patients can safely continue treatment.”
 

More new evidence

Dr. Wilen’s team found that SARS-CoV-2 infection stimulated COX-2 expression in human and mice cells. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication.

In their mouse model of SARS-CoV-2 infection, the investigators saw that NSAIDs impaired the production of proinflammatory cytokines and neutralizing antibodies. The findings suggest that NSAIDs influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies, rather than modifying susceptibility to infection or viral replication.

Understanding the effect of NSAIDs on cytokine production is critical, Dr. Wilen pointed out, because they might be protective early in COVID-19 but pathologic at later stages.

Timing is crucial in the case of other immunomodulatory drugs. For example, dexamethasone lowers mortality in COVID-19 patients on respiratory support but is potentially harmful for those with milder disease.

There still is a lot to learn, Dr. Wilen acknowledged. “We may be seeing something similar going on with NSAIDs, where the timing of treatment is important.”

A version of this article first appeared on Medscape.com.

More people with fever and body aches are turning to NSAIDs to ease symptoms, but the drugs have come under new scrutiny as investigators work to determine whether they are a safe way to relieve the pain of COVID-19 vaccination or symptoms of the disease.

Early on in the pandemic, French health officials warned that NSAIDs, such as ibuprofen, could worsen coronavirus disease, and they recommended switching to acetaminophen instead.

The National Health Service in the United Kingdom followed with a similar recommendation for acetaminophen.

But the European Medicines Agency took a different approach, reporting “no scientific evidence” that NSAIDs could worsen COVID-19. The U.S. Food and Drug Administration also opted not to take a stance.

The debate prompted discussion on social media, with various reactions from around the world. It also inspired Craig Wilen, MD, PhD, from Yale University, New Haven, Conn., and associates to examine the effect of NSAIDs on COVID-19 infection and immune response. Their findings were published online Jan.20 in the Journal of Virology.

“It really bothered me that non–evidence-based decisions were driving the conversation,” Dr. Wilen said. “Millions of people are taking NSAIDs every day and clinical decisions about their care shouldn’t be made on a hypothesis.”

One theory is that NSAIDs alter susceptibility to infection by modifying ACE2. The drugs might also change the cell entry receptor for SARS-CoV-2, alter virus replication, or even modify the immune response.

British researchers, also questioning the safety of NSAIDs in patients with COVID-19, delved into National Health Service records to study two large groups of patients, some of whom were taking the pain relievers.

“We were watching the controversy and the lack of evidence and wanted to contribute,” lead investigator Angel Wong, PhD, from the London School of Hygiene and Tropical Medicine, said in an interview.

And with nearly 11 million NSAID prescriptions dispensed in primary care in England alone in the past 12 months, the inconsistency was concerning.

The team compared COVID-19–related deaths in two groups: one group of more than 700,000 people taking NSAIDs, including patients with rheumatoid arthritis and osteoarthritis; and another of almost 3.5 million people not on the medication.

NSAIDs work by inhibiting cyclooxygenase-1 and COX-2 enzymes in the body, which are crucial for the generation of prostaglandins. These lipid molecules play a role in inflammation and are blocked by NSAIDs.

The investigators found no evidence of a harmful effect of NSAIDs on COVID-19-related deaths; their results were published online Jan. 21 in the Annals of the Rheumatic Diseases.

The results, they pointed out, are in line with a Danish study that also showed no evidence of a higher risk for severe COVID-19 outcomes with NSAID use.

“It’s reassuring,” Dr. Wong said, “that patients can safely continue treatment.”
 

More new evidence

Dr. Wilen’s team found that SARS-CoV-2 infection stimulated COX-2 expression in human and mice cells. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication.

In their mouse model of SARS-CoV-2 infection, the investigators saw that NSAIDs impaired the production of proinflammatory cytokines and neutralizing antibodies. The findings suggest that NSAIDs influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies, rather than modifying susceptibility to infection or viral replication.

Understanding the effect of NSAIDs on cytokine production is critical, Dr. Wilen pointed out, because they might be protective early in COVID-19 but pathologic at later stages.

Timing is crucial in the case of other immunomodulatory drugs. For example, dexamethasone lowers mortality in COVID-19 patients on respiratory support but is potentially harmful for those with milder disease.

There still is a lot to learn, Dr. Wilen acknowledged. “We may be seeing something similar going on with NSAIDs, where the timing of treatment is important.”

A version of this article first appeared on Medscape.com.

More people with fever and body aches are turning to NSAIDs to ease symptoms, but the drugs have come under new scrutiny as investigators work to determine whether they are a safe way to relieve the pain of COVID-19 vaccination or symptoms of the disease.

Early on in the pandemic, French health officials warned that NSAIDs, such as ibuprofen, could worsen coronavirus disease, and they recommended switching to acetaminophen instead.

The National Health Service in the United Kingdom followed with a similar recommendation for acetaminophen.

But the European Medicines Agency took a different approach, reporting “no scientific evidence” that NSAIDs could worsen COVID-19. The U.S. Food and Drug Administration also opted not to take a stance.

The debate prompted discussion on social media, with various reactions from around the world. It also inspired Craig Wilen, MD, PhD, from Yale University, New Haven, Conn., and associates to examine the effect of NSAIDs on COVID-19 infection and immune response. Their findings were published online Jan.20 in the Journal of Virology.

“It really bothered me that non–evidence-based decisions were driving the conversation,” Dr. Wilen said. “Millions of people are taking NSAIDs every day and clinical decisions about their care shouldn’t be made on a hypothesis.”

One theory is that NSAIDs alter susceptibility to infection by modifying ACE2. The drugs might also change the cell entry receptor for SARS-CoV-2, alter virus replication, or even modify the immune response.

British researchers, also questioning the safety of NSAIDs in patients with COVID-19, delved into National Health Service records to study two large groups of patients, some of whom were taking the pain relievers.

“We were watching the controversy and the lack of evidence and wanted to contribute,” lead investigator Angel Wong, PhD, from the London School of Hygiene and Tropical Medicine, said in an interview.

And with nearly 11 million NSAID prescriptions dispensed in primary care in England alone in the past 12 months, the inconsistency was concerning.

The team compared COVID-19–related deaths in two groups: one group of more than 700,000 people taking NSAIDs, including patients with rheumatoid arthritis and osteoarthritis; and another of almost 3.5 million people not on the medication.

NSAIDs work by inhibiting cyclooxygenase-1 and COX-2 enzymes in the body, which are crucial for the generation of prostaglandins. These lipid molecules play a role in inflammation and are blocked by NSAIDs.

The investigators found no evidence of a harmful effect of NSAIDs on COVID-19-related deaths; their results were published online Jan. 21 in the Annals of the Rheumatic Diseases.

The results, they pointed out, are in line with a Danish study that also showed no evidence of a higher risk for severe COVID-19 outcomes with NSAID use.

“It’s reassuring,” Dr. Wong said, “that patients can safely continue treatment.”
 

More new evidence

Dr. Wilen’s team found that SARS-CoV-2 infection stimulated COX-2 expression in human and mice cells. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication.

In their mouse model of SARS-CoV-2 infection, the investigators saw that NSAIDs impaired the production of proinflammatory cytokines and neutralizing antibodies. The findings suggest that NSAIDs influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies, rather than modifying susceptibility to infection or viral replication.

Understanding the effect of NSAIDs on cytokine production is critical, Dr. Wilen pointed out, because they might be protective early in COVID-19 but pathologic at later stages.

Timing is crucial in the case of other immunomodulatory drugs. For example, dexamethasone lowers mortality in COVID-19 patients on respiratory support but is potentially harmful for those with milder disease.

There still is a lot to learn, Dr. Wilen acknowledged. “We may be seeing something similar going on with NSAIDs, where the timing of treatment is important.”

A version of this article first appeared on Medscape.com.

The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.

Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.

“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”

The study was published online Jan. 20 in Neurology.

“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.

The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.

“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
 

Renewing the immune system

The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.

“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”

Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.

Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.

For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.

Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.

Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.

Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.

However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.

In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.

“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
 

Potent and durable efficacy, with caveats

Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”

The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”

He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”

To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.

The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.

Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.

“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”

The study was published online Jan. 20 in Neurology.

“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.

The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.

“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
 

Renewing the immune system

The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.

“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”

Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.

Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.

For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.

Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.

Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.

Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.

However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.

In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.

“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
 

Potent and durable efficacy, with caveats

Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”

The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”

He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”

To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.

The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.

Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.

“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”

The study was published online Jan. 20 in Neurology.

“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.

The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.

“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
 

Renewing the immune system

The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.

“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”

Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.

Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.

For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.

Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.

Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.

Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.

However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.

In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.

“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
 

Potent and durable efficacy, with caveats

Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”

The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”

He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”

To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.

The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Plasma levels of phosphorylated tau at threonine 181 (p-tau181) may provide a means of monitoring disease progression for patients with Alzheimer’s disease, new research suggests.

In a study of more than 1,000 participants, changes over time in levels of p-tau181 were associated with prospective neurodegeneration and cognitive decline characteristic of Alzheimer’s disease. These results have implications for investigative trials as well as clinical practice, the investigators noted.

Like p-tau181, neurofilament light chain (NfL) is associated with imaging markers of degeneration and cognitive decline; in contrast to the findings related to p-tau181, however, the associations between NfL and these outcomes are not specific to Alzheimer’s disease. Using both biomarkers could improve prediction of outcomes and patient monitoring, according to the researchers.

“These findings demonstrate that p-tau181 and NfL in blood have individual and complementary potential roles in the diagnosis and the monitoring of neurodegenerative disease,” said coinvestigator Michael Schöll, PhD, senior lecturer in psychiatry and neurochemistry at the University of Gothenburg (Sweden).

“With the reservation that we did not assess domain-specific cognitive impairment, p-tau181 was also more strongly associated with cognitive decline than was NfL,” Dr. Schöll added.

The findings were published online Jan. 11 in JAMA Neurology.
 

Biomarker-tracked neurodegeneration

Monitoring a patient’s neurodegenerative changes is important for tracking Alzheimer’s disease progression. Although clinicians can detect amyloid-beta and tau pathology using PET and cerebrospinal fluid (CSF) biomarkers, the widespread use of the latter has been hampered by cost and limited availability of necessary equipment. The use of blood-based biomarkers is not limited in these ways, and so they could aid in diagnosis and patient monitoring.

Previous studies have suggested that p-tau181 is a marker of Alzheimer’s disease status.

In the current study, investigators examined whether baseline and longitudinal levels of p-tau181 in plasma were associated with progressive neurodegeneration related to the disease. They analyzed data from the Alzheimer’s Disease Neuroimaging Initiative, a multicenter study designed to identify biomarkers for the detection and tracking of Alzheimer’s disease.

The researchers selected data for cognitively unimpaired and cognitively impaired participants who participated in the initiative between Feb. 1, 2007, and June 6, 2016. Participants were eligible for inclusion if plasma p-tau181 and NfL data were available for them and if they had undergone at least one 18fluorodeoxyglucose (FDG)–PET scan or structural T1 MRI at the same study visit. Most had also undergone imaging with 18florbetapir, which detects amyloid-beta.

A single-molecule array was used to analyze concentrations of p-tau181 and NfL in participants’ blood samples. Outliers for p-tau181 and NfL concentrations were excluded from further analysis. Using participants’ FDG-PET scans, the investigators measured glucose hypometabolism characteristic of Alzheimer’s disease. They used T1-weighted MRI scans to measure gray-matter volume.

Cognitively unimpaired participants responded to the Preclinical Alzheimer Cognitive Composite, a measure designed to detect early cognitive changes in cognitively normal patients with Alzheimer’s disease pathology. Cognitively impaired participants underwent the Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks to assess the severity of cognitive impairment.

The researchers included 1,113 participants (54% men; 89% non-Hispanic Whites; mean age, 74 years) in their analysis. In all, 378 participants were cognitively unimpaired, and 735 were cognitively impaired. Of the latter group, 73% had mild cognitive impairment, and 27% had Alzheimer’s disease dementia.
 

Atrophy predictor

Results showed that higher plasma p-tau181 levels at baseline were associated with more rapid progression of hypometabolism and atrophy in areas vulnerable to Alzheimer’s disease among cognitively impaired participants (FDG-PET standardized uptake value ratio change, r = –0.28; P < .001; gray-matter volume change, r = –0.28; P < .001).

The association with atrophy progression in cognitively impaired participants was stronger for p-tau181 than for NfL.

Plasma p-tau181 levels at baseline also predicted atrophy in temporoparietal regions vulnerable to Alzheimer’s disease among cognitively unimpaired participants (r = –0.11; P = .03). NfL, however, was associated with progressive atrophy in frontal regions among cognitively unimpaired participants.

At baseline, plasma p-tau181 levels were associated with prospective cognitive decline in both the cognitively unimpaired group (r = −0.12; P = .04) and the cognitively impaired group (r = 0.35; P < .001). However, plasma NfL was linked to cognitive decline only among those who were cognitively impaired (r = 0.26; P < .001).

Additional analyses showed that p-tau181, unlike NfL, was associated with hypometabolism and atrophy only in participants with amyloid-beta, regardless of cognitive status.

Between 25% and 45% of the association between baseline p-tau181 level and cognitive decline was mediated by baseline imaging markers of neurodegeneration. This finding suggests that another factor, such as regional tau pathology, might have an independent and direct effect on cognition, Dr. Schöll noted.

Furthermore, changes over time in p-tau181 levels were associated with cognitive decline in the cognitively unimpaired (r = –0.24; P < .001) and cognitively impaired (r = 0.34; P < .001) participants. Longitudinal changes in this biomarker also were associated with a prospective decrease in glucose metabolism in cognitively unimpaired (r = –0.05; P = .48) and cognitively impaired (r = –0.27; P < .001) participants, but the association was only significant in the latter group.

Changes over time in p-tau181 levels were linked to prospective decreases in gray-matter volume in brain regions highly characteristic of Alzheimer’s disease in those who were cognitively unimpaired (r = –0.19; P < .001) and those who were cognitively impaired (r = –0.31, P < .001). However, these associations were obtained only in patients with amyloid-beta.

Dr. Schöll noted that blood-based biomarkers that are sensitive to Alzheimer’s disease could greatly expand patients’ access to a diagnostic workup and could improve screening for clinical trials.

“While the final validation of the existence and the monitoring of potential changes of neuropathology in vivo is likely to be conducted using neuroimaging modalities such as PET, our results suggest that at least a part of these examinations could be replaced by regular blood tests,” Dr. Schöll said.

Lead author Alexis Moscoso, PhD, a postdoctoral researcher in psychiatry and neurochemistry at the University of Gothenburg, reported that the researchers will continue validating blood-based biomarkers, especially against established and well-validated neuroimaging methods. “We are also hoping to be able to compare existing and novel blood-based Alzheimer’s disease biomarkers head to head to establish the individual roles each of these play in the research and diagnosis of Alzheimer’s disease,” Dr. Moscoso said.
 

‘Outstanding study’

Commenting on the findings, David S. Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., said that this is “an outstanding study” because of its large number of participants and because the investigators are “world leaders in the technology of measuring plasma p-tau and NfL.”

Dr. Knopman, who was not involved with the research, noted that the study had no substantive weaknesses.

“The biggest advantages of a blood-based biomarker over CSF- and PET-based biomarkers of Alzheimer disease are the obvious ones of accessibility, cost, portability, and ease of repeatability,” he said.

“As CSF and PET exams are largely limited to major medical centers, valid blood-based biomarkers of Alzheimer disease that are reasonably specific make large-scale epidemiological studies that investigate dementia etiologies in rural or urban and diverse communities feasible,” he added.

Whereas p-tau181 appears to be specific for plaque and tangle disease, NfL is a nonspecific marker of neurodegeneration.

“Each has a role that could be valuable, depending on the circumstance,” said Dr. Knopman. “Plasma NfL has already proved itself useful in frontotemporal degeneration and chronic traumatic encephalopathy, for example.”

He noted that future studies should examine how closely p-tau181 and NfL align with more granular and direct measures of Alzheimer’s disease–related brain pathologies.

“There has got to be some loss of fidelity in detecting abnormality in going from brain tissue to blood, which might siphon off some time-related and severity-related information,” said Dr. Knopman.

“The exact role that plasma p-tau and NfL will play remains to be seen, because the diagnostic information that these biomarkers provide is contingent on the existence of interventions that require specific or nonspecific information about progressive neurodegeneration due to Alzheimer disease,” he added.

The study was funded by grants from the Spanish Instituto de Salud Carlos III, the Brightfocus Foundation, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. Dr. Schöll reported serving on a scientific advisory board for Servier on matters unrelated to this study. Dr. Moscoso and Dr. Knopman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Plasma levels of phosphorylated tau at threonine 181 (p-tau181) may provide a means of monitoring disease progression for patients with Alzheimer’s disease, new research suggests.

In a study of more than 1,000 participants, changes over time in levels of p-tau181 were associated with prospective neurodegeneration and cognitive decline characteristic of Alzheimer’s disease. These results have implications for investigative trials as well as clinical practice, the investigators noted.

Like p-tau181, neurofilament light chain (NfL) is associated with imaging markers of degeneration and cognitive decline; in contrast to the findings related to p-tau181, however, the associations between NfL and these outcomes are not specific to Alzheimer’s disease. Using both biomarkers could improve prediction of outcomes and patient monitoring, according to the researchers.

“These findings demonstrate that p-tau181 and NfL in blood have individual and complementary potential roles in the diagnosis and the monitoring of neurodegenerative disease,” said coinvestigator Michael Schöll, PhD, senior lecturer in psychiatry and neurochemistry at the University of Gothenburg (Sweden).

“With the reservation that we did not assess domain-specific cognitive impairment, p-tau181 was also more strongly associated with cognitive decline than was NfL,” Dr. Schöll added.

The findings were published online Jan. 11 in JAMA Neurology.
 

Biomarker-tracked neurodegeneration

Monitoring a patient’s neurodegenerative changes is important for tracking Alzheimer’s disease progression. Although clinicians can detect amyloid-beta and tau pathology using PET and cerebrospinal fluid (CSF) biomarkers, the widespread use of the latter has been hampered by cost and limited availability of necessary equipment. The use of blood-based biomarkers is not limited in these ways, and so they could aid in diagnosis and patient monitoring.

Previous studies have suggested that p-tau181 is a marker of Alzheimer’s disease status.

In the current study, investigators examined whether baseline and longitudinal levels of p-tau181 in plasma were associated with progressive neurodegeneration related to the disease. They analyzed data from the Alzheimer’s Disease Neuroimaging Initiative, a multicenter study designed to identify biomarkers for the detection and tracking of Alzheimer’s disease.

The researchers selected data for cognitively unimpaired and cognitively impaired participants who participated in the initiative between Feb. 1, 2007, and June 6, 2016. Participants were eligible for inclusion if plasma p-tau181 and NfL data were available for them and if they had undergone at least one 18fluorodeoxyglucose (FDG)–PET scan or structural T1 MRI at the same study visit. Most had also undergone imaging with 18florbetapir, which detects amyloid-beta.

A single-molecule array was used to analyze concentrations of p-tau181 and NfL in participants’ blood samples. Outliers for p-tau181 and NfL concentrations were excluded from further analysis. Using participants’ FDG-PET scans, the investigators measured glucose hypometabolism characteristic of Alzheimer’s disease. They used T1-weighted MRI scans to measure gray-matter volume.

Cognitively unimpaired participants responded to the Preclinical Alzheimer Cognitive Composite, a measure designed to detect early cognitive changes in cognitively normal patients with Alzheimer’s disease pathology. Cognitively impaired participants underwent the Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks to assess the severity of cognitive impairment.

The researchers included 1,113 participants (54% men; 89% non-Hispanic Whites; mean age, 74 years) in their analysis. In all, 378 participants were cognitively unimpaired, and 735 were cognitively impaired. Of the latter group, 73% had mild cognitive impairment, and 27% had Alzheimer’s disease dementia.
 

Atrophy predictor

Results showed that higher plasma p-tau181 levels at baseline were associated with more rapid progression of hypometabolism and atrophy in areas vulnerable to Alzheimer’s disease among cognitively impaired participants (FDG-PET standardized uptake value ratio change, r = –0.28; P < .001; gray-matter volume change, r = –0.28; P < .001).

The association with atrophy progression in cognitively impaired participants was stronger for p-tau181 than for NfL.

Plasma p-tau181 levels at baseline also predicted atrophy in temporoparietal regions vulnerable to Alzheimer’s disease among cognitively unimpaired participants (r = –0.11; P = .03). NfL, however, was associated with progressive atrophy in frontal regions among cognitively unimpaired participants.

At baseline, plasma p-tau181 levels were associated with prospective cognitive decline in both the cognitively unimpaired group (r = −0.12; P = .04) and the cognitively impaired group (r = 0.35; P < .001). However, plasma NfL was linked to cognitive decline only among those who were cognitively impaired (r = 0.26; P < .001).

Additional analyses showed that p-tau181, unlike NfL, was associated with hypometabolism and atrophy only in participants with amyloid-beta, regardless of cognitive status.

Between 25% and 45% of the association between baseline p-tau181 level and cognitive decline was mediated by baseline imaging markers of neurodegeneration. This finding suggests that another factor, such as regional tau pathology, might have an independent and direct effect on cognition, Dr. Schöll noted.

Furthermore, changes over time in p-tau181 levels were associated with cognitive decline in the cognitively unimpaired (r = –0.24; P < .001) and cognitively impaired (r = 0.34; P < .001) participants. Longitudinal changes in this biomarker also were associated with a prospective decrease in glucose metabolism in cognitively unimpaired (r = –0.05; P = .48) and cognitively impaired (r = –0.27; P < .001) participants, but the association was only significant in the latter group.

Changes over time in p-tau181 levels were linked to prospective decreases in gray-matter volume in brain regions highly characteristic of Alzheimer’s disease in those who were cognitively unimpaired (r = –0.19; P < .001) and those who were cognitively impaired (r = –0.31, P < .001). However, these associations were obtained only in patients with amyloid-beta.

Dr. Schöll noted that blood-based biomarkers that are sensitive to Alzheimer’s disease could greatly expand patients’ access to a diagnostic workup and could improve screening for clinical trials.

“While the final validation of the existence and the monitoring of potential changes of neuropathology in vivo is likely to be conducted using neuroimaging modalities such as PET, our results suggest that at least a part of these examinations could be replaced by regular blood tests,” Dr. Schöll said.

Lead author Alexis Moscoso, PhD, a postdoctoral researcher in psychiatry and neurochemistry at the University of Gothenburg, reported that the researchers will continue validating blood-based biomarkers, especially against established and well-validated neuroimaging methods. “We are also hoping to be able to compare existing and novel blood-based Alzheimer’s disease biomarkers head to head to establish the individual roles each of these play in the research and diagnosis of Alzheimer’s disease,” Dr. Moscoso said.
 

‘Outstanding study’

Commenting on the findings, David S. Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., said that this is “an outstanding study” because of its large number of participants and because the investigators are “world leaders in the technology of measuring plasma p-tau and NfL.”

Dr. Knopman, who was not involved with the research, noted that the study had no substantive weaknesses.

“The biggest advantages of a blood-based biomarker over CSF- and PET-based biomarkers of Alzheimer disease are the obvious ones of accessibility, cost, portability, and ease of repeatability,” he said.

“As CSF and PET exams are largely limited to major medical centers, valid blood-based biomarkers of Alzheimer disease that are reasonably specific make large-scale epidemiological studies that investigate dementia etiologies in rural or urban and diverse communities feasible,” he added.

Whereas p-tau181 appears to be specific for plaque and tangle disease, NfL is a nonspecific marker of neurodegeneration.

“Each has a role that could be valuable, depending on the circumstance,” said Dr. Knopman. “Plasma NfL has already proved itself useful in frontotemporal degeneration and chronic traumatic encephalopathy, for example.”

He noted that future studies should examine how closely p-tau181 and NfL align with more granular and direct measures of Alzheimer’s disease–related brain pathologies.

“There has got to be some loss of fidelity in detecting abnormality in going from brain tissue to blood, which might siphon off some time-related and severity-related information,” said Dr. Knopman.

“The exact role that plasma p-tau and NfL will play remains to be seen, because the diagnostic information that these biomarkers provide is contingent on the existence of interventions that require specific or nonspecific information about progressive neurodegeneration due to Alzheimer disease,” he added.

The study was funded by grants from the Spanish Instituto de Salud Carlos III, the Brightfocus Foundation, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. Dr. Schöll reported serving on a scientific advisory board for Servier on matters unrelated to this study. Dr. Moscoso and Dr. Knopman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Plasma levels of phosphorylated tau at threonine 181 (p-tau181) may provide a means of monitoring disease progression for patients with Alzheimer’s disease, new research suggests.

In a study of more than 1,000 participants, changes over time in levels of p-tau181 were associated with prospective neurodegeneration and cognitive decline characteristic of Alzheimer’s disease. These results have implications for investigative trials as well as clinical practice, the investigators noted.

Like p-tau181, neurofilament light chain (NfL) is associated with imaging markers of degeneration and cognitive decline; in contrast to the findings related to p-tau181, however, the associations between NfL and these outcomes are not specific to Alzheimer’s disease. Using both biomarkers could improve prediction of outcomes and patient monitoring, according to the researchers.

“These findings demonstrate that p-tau181 and NfL in blood have individual and complementary potential roles in the diagnosis and the monitoring of neurodegenerative disease,” said coinvestigator Michael Schöll, PhD, senior lecturer in psychiatry and neurochemistry at the University of Gothenburg (Sweden).

“With the reservation that we did not assess domain-specific cognitive impairment, p-tau181 was also more strongly associated with cognitive decline than was NfL,” Dr. Schöll added.

The findings were published online Jan. 11 in JAMA Neurology.
 

Biomarker-tracked neurodegeneration

Monitoring a patient’s neurodegenerative changes is important for tracking Alzheimer’s disease progression. Although clinicians can detect amyloid-beta and tau pathology using PET and cerebrospinal fluid (CSF) biomarkers, the widespread use of the latter has been hampered by cost and limited availability of necessary equipment. The use of blood-based biomarkers is not limited in these ways, and so they could aid in diagnosis and patient monitoring.

Previous studies have suggested that p-tau181 is a marker of Alzheimer’s disease status.

In the current study, investigators examined whether baseline and longitudinal levels of p-tau181 in plasma were associated with progressive neurodegeneration related to the disease. They analyzed data from the Alzheimer’s Disease Neuroimaging Initiative, a multicenter study designed to identify biomarkers for the detection and tracking of Alzheimer’s disease.

The researchers selected data for cognitively unimpaired and cognitively impaired participants who participated in the initiative between Feb. 1, 2007, and June 6, 2016. Participants were eligible for inclusion if plasma p-tau181 and NfL data were available for them and if they had undergone at least one 18fluorodeoxyglucose (FDG)–PET scan or structural T1 MRI at the same study visit. Most had also undergone imaging with 18florbetapir, which detects amyloid-beta.

A single-molecule array was used to analyze concentrations of p-tau181 and NfL in participants’ blood samples. Outliers for p-tau181 and NfL concentrations were excluded from further analysis. Using participants’ FDG-PET scans, the investigators measured glucose hypometabolism characteristic of Alzheimer’s disease. They used T1-weighted MRI scans to measure gray-matter volume.

Cognitively unimpaired participants responded to the Preclinical Alzheimer Cognitive Composite, a measure designed to detect early cognitive changes in cognitively normal patients with Alzheimer’s disease pathology. Cognitively impaired participants underwent the Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks to assess the severity of cognitive impairment.

The researchers included 1,113 participants (54% men; 89% non-Hispanic Whites; mean age, 74 years) in their analysis. In all, 378 participants were cognitively unimpaired, and 735 were cognitively impaired. Of the latter group, 73% had mild cognitive impairment, and 27% had Alzheimer’s disease dementia.
 

Atrophy predictor

Results showed that higher plasma p-tau181 levels at baseline were associated with more rapid progression of hypometabolism and atrophy in areas vulnerable to Alzheimer’s disease among cognitively impaired participants (FDG-PET standardized uptake value ratio change, r = –0.28; P < .001; gray-matter volume change, r = –0.28; P < .001).

The association with atrophy progression in cognitively impaired participants was stronger for p-tau181 than for NfL.

Plasma p-tau181 levels at baseline also predicted atrophy in temporoparietal regions vulnerable to Alzheimer’s disease among cognitively unimpaired participants (r = –0.11; P = .03). NfL, however, was associated with progressive atrophy in frontal regions among cognitively unimpaired participants.

At baseline, plasma p-tau181 levels were associated with prospective cognitive decline in both the cognitively unimpaired group (r = −0.12; P = .04) and the cognitively impaired group (r = 0.35; P < .001). However, plasma NfL was linked to cognitive decline only among those who were cognitively impaired (r = 0.26; P < .001).

Additional analyses showed that p-tau181, unlike NfL, was associated with hypometabolism and atrophy only in participants with amyloid-beta, regardless of cognitive status.

Between 25% and 45% of the association between baseline p-tau181 level and cognitive decline was mediated by baseline imaging markers of neurodegeneration. This finding suggests that another factor, such as regional tau pathology, might have an independent and direct effect on cognition, Dr. Schöll noted.

Furthermore, changes over time in p-tau181 levels were associated with cognitive decline in the cognitively unimpaired (r = –0.24; P < .001) and cognitively impaired (r = 0.34; P < .001) participants. Longitudinal changes in this biomarker also were associated with a prospective decrease in glucose metabolism in cognitively unimpaired (r = –0.05; P = .48) and cognitively impaired (r = –0.27; P < .001) participants, but the association was only significant in the latter group.

Changes over time in p-tau181 levels were linked to prospective decreases in gray-matter volume in brain regions highly characteristic of Alzheimer’s disease in those who were cognitively unimpaired (r = –0.19; P < .001) and those who were cognitively impaired (r = –0.31, P < .001). However, these associations were obtained only in patients with amyloid-beta.

Dr. Schöll noted that blood-based biomarkers that are sensitive to Alzheimer’s disease could greatly expand patients’ access to a diagnostic workup and could improve screening for clinical trials.

“While the final validation of the existence and the monitoring of potential changes of neuropathology in vivo is likely to be conducted using neuroimaging modalities such as PET, our results suggest that at least a part of these examinations could be replaced by regular blood tests,” Dr. Schöll said.

Lead author Alexis Moscoso, PhD, a postdoctoral researcher in psychiatry and neurochemistry at the University of Gothenburg, reported that the researchers will continue validating blood-based biomarkers, especially against established and well-validated neuroimaging methods. “We are also hoping to be able to compare existing and novel blood-based Alzheimer’s disease biomarkers head to head to establish the individual roles each of these play in the research and diagnosis of Alzheimer’s disease,” Dr. Moscoso said.
 

‘Outstanding study’

Commenting on the findings, David S. Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., said that this is “an outstanding study” because of its large number of participants and because the investigators are “world leaders in the technology of measuring plasma p-tau and NfL.”

Dr. Knopman, who was not involved with the research, noted that the study had no substantive weaknesses.

“The biggest advantages of a blood-based biomarker over CSF- and PET-based biomarkers of Alzheimer disease are the obvious ones of accessibility, cost, portability, and ease of repeatability,” he said.

“As CSF and PET exams are largely limited to major medical centers, valid blood-based biomarkers of Alzheimer disease that are reasonably specific make large-scale epidemiological studies that investigate dementia etiologies in rural or urban and diverse communities feasible,” he added.

Whereas p-tau181 appears to be specific for plaque and tangle disease, NfL is a nonspecific marker of neurodegeneration.

“Each has a role that could be valuable, depending on the circumstance,” said Dr. Knopman. “Plasma NfL has already proved itself useful in frontotemporal degeneration and chronic traumatic encephalopathy, for example.”

He noted that future studies should examine how closely p-tau181 and NfL align with more granular and direct measures of Alzheimer’s disease–related brain pathologies.

“There has got to be some loss of fidelity in detecting abnormality in going from brain tissue to blood, which might siphon off some time-related and severity-related information,” said Dr. Knopman.

“The exact role that plasma p-tau and NfL will play remains to be seen, because the diagnostic information that these biomarkers provide is contingent on the existence of interventions that require specific or nonspecific information about progressive neurodegeneration due to Alzheimer disease,” he added.

The study was funded by grants from the Spanish Instituto de Salud Carlos III, the Brightfocus Foundation, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. Dr. Schöll reported serving on a scientific advisory board for Servier on matters unrelated to this study. Dr. Moscoso and Dr. Knopman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.